{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T21:36:25Z","timestamp":1781732185406,"version":"3.54.5"},"reference-count":7,"publisher":"S. Karger AG","issue":"10","license":[{"start":{"date-parts":[[2021,1,1]],"date-time":"2021-01-01T00:00:00Z","timestamp":1609459200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.karger.com\/Services\/SiteLicenses"},{"start":{"date-parts":[[2021,1,1]],"date-time":"2021-01-01T00:00:00Z","timestamp":1609459200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.karger.com\/Services\/SiteLicenses"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Oncol Res Treat"],"published-print":{"date-parts":[[2021]]},"abstract":"<b><i>Purpose:<\/i><\/b> This first-in-human study (NCT02947152) evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of HKT288, a first-in-class CDH6-targeting antibody-drug conjugate (ADC). <b><i>Experimental Design:<\/i><\/b> HKT288 was administered intravenously (IV) every 3 weeks until patients experienced unacceptable toxicity or progressive disease (PD). The starting dose of 0.3 mg\/kg was determined based on the highest nonseverely toxic dose in monkeys, which was 2 mg\/kg IV weekly. Based on preclinical toxicology, skin, eyes, bone marrow, and liver were expected targets of toxicity. <b><i>Results:<\/i><\/b> Nine patients were enrolled: 5 with renal cell carcinoma and 4 with epithelial ovarian cancer. The best overall response on the 0.3 mg\/kg cohort in patients with measurable disease was RECIST v1.1 stable disease in 3 patients and PD in 2 patients. The most frequent adverse events (AEs) regardless of causality were pyrexia (44.4%), constipation (44.4%), fatigue (33.3%), and vomiting (33.3%). Three suspected-related neurologic AEs (Grade 2) were reported on the 0.75 mg\/kg cohort: seizure in 1 patient and another patient with aphasia and encephalopathy. Further studies were unable to identify the underlying mechanism of the neurologic AEs, and the study was terminated early. <b><i>Conclusions:<\/i><\/b> Preclinical toxicology did not predict the neurotoxicity observed with HKT288, and a comprehensive assessment performed post hoc did not identify the mechanism of toxicity. The development of further CDH6-targeting ADCs should be pursued with caution. <\/jats:p>","DOI":"10.1159\/000518549","type":"journal-article","created":{"date-parts":[[2021,8,19]],"date-time":"2021-08-19T21:00:45Z","timestamp":1629406845000},"page":"547-556","source":"Crossref","is-referenced-by-count":28,"title":["A Phase 1 Study of a CDH6-Targeting Antibody-Drug Conjugate in Patients with Advanced Solid Tumors with Evaluation of Inflammatory and Neurological Adverse Events"],"prefix":"10.1159","volume":"44","author":[{"given":"Patrick","family":"Sch\u00f6ffski","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Concin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Suarez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6064-6837","authenticated-orcid":false,"given":"Vivek","family":"Subbiah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuichi","family":"Ando","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiling","family":"Ruan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel P.","family":"Wagner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith","family":"Mansfield","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shizuka","family":"Origuchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"DiDominick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carl U.","family":"Bialucha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason E.","family":"Faris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben","family":"Tran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"127","published-online":{"date-parts":[[2021,8,19]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-16-1414"},{"key":"ref2","doi-asserted-by":"publisher","DOI":"10.1089\/jop.2015.0064"},{"key":"ref3","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-17-0698"},{"key":"ref4","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-16-0040"},{"key":"ref5","doi-asserted-by":"publisher","DOI":"10.1080\/1744666X.2017.1384313"},{"key":"ref6","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.1006"},{"key":"ref7","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2018.03.009"}],"container-title":["Oncology Research and Treatment"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.karger.com\/Article\/Pdf\/518549","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.karger.com\/Article\/Pdf\/518549","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T15:16:55Z","timestamp":1745421415000},"score":1,"resource":{"primary":{"URL":"https:\/\/karger.com\/article\/doi\/10.1159\/000518549"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021]]},"references-count":7,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2021,10,1]]},"published-print":{"date-parts":[[2021,10,19]]}},"URL":"https:\/\/doi.org\/10.1159\/000518549","archive":["Portico"],"relation":{"is-supplemented-by":[{"id-type":"doi","id":"10.6084\/m9.figshare.15257394","asserted-by":"subject"}]},"ISSN":["2296-5270","2296-5262"],"issn-type":[{"value":"2296-5270","type":"print"},{"value":"2296-5262","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021]]}}}